Comparison of the Effect of Cilostazol with Aspirin on Circulating Endothelial Progenitor Cells and Small-Dense LDL Cholesterol in Diabetic Patients with Cerebral Ischemia: A Randomized Controlled Pilot Trial

Abstract

Aim:A recent clinical trial showed the preventive effect of cilostazol on cerebrovascular diseases. We compared the effects of cilostazol with aspirin on circulating endothelial progenitor cells (EPCs), a surrogate marker for cardiovascular disease, and lipid metabolism in a randomized controlled trial (UMIN000000537). Methods: Forty-nine diabetic outpatients with leukoaraiosis or asymptomatic old cerebral infarction were enrolled in the study with written informed consent. They were randomly assigned to a cilostazol (200 mg daily, n 24) or aspirin group (100 mg daily, n 25), and followed for 16 weeks. Changes in circulating CD34 CD45 low CD133 VEGFR2 EPCs ( EPC) were a primary endpoint. Changes in CD34 CD45 low CD133 progenitor cells ( PC), p-selectin-positive platelet, plateletmonocyte binding measured by flow cytometry, LDL-, HDL-, small dense LDL (sdLDL)-cholesterol and triacylglycerol were the secondary endpoints. Results: Twenty patients in each group completed the study. EPC were significantly higher in the cilostazol group than aspirin group at 16 weeks, while PC were already significantly higher at 4 weeks in the cilostazol group. Changes in p-selectin-positive platelets and platelet-monocyte binding were similar in both groups. The cilostazol group showed significantly less sdLDL-and higher HDLcholesterol than the aspirin group at both 4 and 16 weeks. EPC were significantly and inversely correlated with changes of sdLDL, while positively with those of HDL. Analysis of covariance showed that a significant relation of EPCs with cilostazol treatment was confounded by changes in HDL-and sdLDL-cholesterol. Conclusion: Cilostazol increases circulating EPCs and decreases small-dense LDL in diabetic patients with cerebral ischemia. J Atheroscler Thromb, 2011; 18:883-890.

Macro‐ and microvascular endothelial dysfunction in diabetes

“…In diabetic patients, cilostazol reduces soluble CD40 ligand and thrombomodulin levels in the serum, leading to a reduction of restenosis after percutaneous transluminal coronary angioplasty . Cilostazol also improves the function of circulating endothelial progenitor cells in diabetic patients with ischemic cerebrovascular disease . The protective effects of cilostazol are attributable to upregulation of peroxisome proliferator‐activated receptor (PPAR) γ and eNOS, downregulation of VCAM, or blockade of the TNF pathway …”

The Blood Glucose Level Increased in Parallel with the Heart Rate Following Cilostazol Administration in Three Diabetic Patients

“…Clinical studies evaluating the effects of cilostazol on glycemic control are scarce. Randomized controlled studies of cilostazol therapy in diabetic patients (19)(20)(21) demonstrated no significant changes in the HbA1c and glucose levels; however, the anti-diabetic therapy used in these studies did not necessarily remain unchanged because the studies did not aim to evaluate glycemic control.…”

Adjunctive Cilostazol to Dual Antiplatelet Therapy to Enhance Mobilization of Endothelial Progenitor Cell in Patients with Acute Myocardial Infarction: A Randomized, Placebo-Controlled EPISODE Trial

“…There have been no studies to evaluate the effect of cilostazol on EPC mobilization in patients with AMI. Therefore, the sample size calculation was based on a previous study evaluating the EPC-mobilizing effect of cilostazol versus aspirin in diabetic patients with cerebral ischemia [32]. After four-month treatment, the relative increase in EPC count was about 50% higher in the cilostazol users compared with the aspirin users (101.8% versus 50.6%).…”